KR101653064B1 - A Method for Gadobutrol - Google Patents
A Method for Gadobutrol Download PDFInfo
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- KR101653064B1 KR101653064B1 KR1020140190833A KR20140190833A KR101653064B1 KR 101653064 B1 KR101653064 B1 KR 101653064B1 KR 1020140190833 A KR1020140190833 A KR 1020140190833A KR 20140190833 A KR20140190833 A KR 20140190833A KR 101653064 B1 KR101653064 B1 KR 101653064B1
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- 238000000034 method Methods 0.000 title claims abstract description 21
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 title abstract description 14
- 229960003411 gadobutrol Drugs 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000011347 resin Substances 0.000 claims description 7
- 229920005989 resin Polymers 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- 229940075613 gadolinium oxide Drugs 0.000 claims description 4
- 229910001938 gadolinium oxide Inorganic materials 0.000 claims description 4
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical compound Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 claims description 2
- LYQGMALGKYWNIU-UHFFFAOYSA-K gadolinium(3+);triacetate Chemical compound [Gd+3].CC([O-])=O.CC([O-])=O.CC([O-])=O LYQGMALGKYWNIU-UHFFFAOYSA-K 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 239000000543 intermediate Substances 0.000 abstract 1
- -1 2,3-dihydroxy-1- (hydroxymethyl) propyl Chemical group 0.000 description 8
- 239000008213 purified water Substances 0.000 description 7
- 229910052688 Gadolinium Inorganic materials 0.000 description 6
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- JZNZSKXIEDHOBD-HUUCEWRRSA-N 2-[4,10-bis(carboxymethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC[C@@H](O)[C@@H](CO)N1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 JZNZSKXIEDHOBD-HUUCEWRRSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- ZPDFIIGFYAHNSK-UHFFFAOYSA-K gadobutrol Chemical compound [Gd+3].OCC(O)C(CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-UHFFFAOYSA-K 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ARXKVVRQIIOZGF-UHFFFAOYSA-N 1,2,4-butanetriol Chemical compound OCCC(O)CO ARXKVVRQIIOZGF-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Radiology & Medical Imaging (AREA)
- Medicinal Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Steroid Compounds (AREA)
Abstract
본 발명은 고순도의 가도부트롤을 제조하는 신규한 방법을 제공한다. 본 발명은 간단하고 온화한 공정으로 중간체의 순도를 관리할 수 있어 기존의 순도보다 높은 고순도 또는 초고순도를 가지는 가도부트롤을 높은 수율로 수득할 수 있어 대량 생산에 용이하게 적용될 수 있다.The present invention provides a novel process for preparing high purity talb trolls. The present invention can manage the purity of intermediates by a simple and mild process, and can produce gadobutrol having high purity or ultrahigh purity higher than conventional purity at a high yield, and thus can be easily applied to mass production.
Description
본 발명은 가도부트롤의 신규 제조방법에 관한 것이다. 구체적으로, 본 발명은 기존 합성방법과 달리 중간체의 순도를 관리하여 고순도의 가도부트롤을 제조하는 방법에 관한 것이다.The present invention relates to a novel process for preparing gadobutrol. Specifically, the present invention relates to a method for preparing high purity Gaobbutrol by controlling the purity of the intermediate, unlike the conventional synthesis method.
가돌리늄(Gadolinium) 함유 조영제(contrast agent) 분야에서 가도부트롤(Gadobutrol)은 가도비스트(Gadovist) 또는 가다비스트(Gadavist)라는 상품명으로 전세계에서 시판 중이다.In the field of contrast agent containing Gadolinium, Gadobutrol is marketed worldwide under the trade name Gadovist or Gadavist.
하기 화학식 1로 표시되는 가도부트롤은 마이크로시클릭 리간드 10-(2,3-디히드록시-1-(히드록시메틸)프로필)-1,4,7,10-테트라아자시클로데칸-1,4,7-트리아세트산(부트롤)과 가돌리늄(III)의 비-이온성 착물이며, 이것은 특히 임상적으로 권장되는 용량에서 조직수 중 프로톤의 완화시간의 단축을 유발한다.The gadobutrol represented by the following formula (1) is a microcyclic ligand: 10- (2,3-dihydroxy-1- (hydroxymethyl) propyl) -1,4,7,10-tetraazacyclodecane- Is a non-ionic complex of 4,7-triacetic acid (butrol) and gadolinium (III), which leads to a reduction in the relaxation time of protons in the tissue water, especially at clinically recommended doses.
[화학식 1][Chemical Formula 1]
가도부트롤의 합성방법은 Inorg. Chem. 1997, 36, 6086-6093 에 3가지 경로(스킴 1 내지 3)가 자세히 기술되어 있다. 상기 문헌에서 스킴 3의 경로는 수율이 낮아 대량생산의 면에서 부적합하다고 기재되어 있다. 따라서, 스킴 3의 경로는 실험실 수준에 고려할 수 있는 수준이며, 대량생산시에는 배제하여야 함이 통상의 기술자에게 널리 인식되어 알려져 있었다. 한편, 스킴 1의 경우 정제를 위하여 많은 양의 레진을 사용해야 하며, 그에 따른 tower 등의 특수 시설을 갖추어야 하는 단점이 있다. 따라서, 스킴 1의 방법은 단가 상승으로 인하여 대량생산에 적용하기 곤란하다. 또한, 스킴 2의 경우 수율이 낮으며, 순도도 좋지 못한 문제점이 있다.The synthesis of gadobutrol is described in Inorg. Chem. 1997, 36, 6086-6093, three routes (schemes 1 to 3) are described in detail. In this document, it is described that the route of Scheme 3 is inadequate in terms of mass production because of low yield. Therefore, it has been widely known to those skilled in the art that the path of Scheme 3 is a level that can be considered at the laboratory level and should be excluded at the time of mass production. On the other hand, in Scheme 1, a large amount of resin must be used for refining and there is a disadvantage that special facilities such as a tower should be provided. Therefore, the method of Scheme 1 is difficult to apply to mass production due to an increase in unit price. In case of Scheme 2, the yield is low and the purity is poor.
ICH 가이드라인 등 국제기준에서는 불순물 함량이 0.1% 이하가 되도록 권장하고 있으므로, 가도부트롤이 의약품으로 판매되기 위해서는 순도가 99.9% 이상의 초고순도로 제조되는 것이 바람직하다. 그러나, 상기 문헌에 개시된 방법은 공정이 복잡하고 고순도의 가도부트롤을 제조할 수 없다.It is recommended that the impurity content be less than 0.1% in the international standards such as ICH guidelines. Therefore, it is preferable that the gadobutrol is manufactured with a purity of 99.9% or more in order to be sold as a pharmaceutical product. However, the process disclosed in the above document can not produce a high-purity Gaobbutrol with a complicated process.
따라서, 복잡한 정제 공정 없이 제조 공정이 단순하면서 고 순도의 가도부트롤을 고 수율로 제조할 수 있고, 결국 대량생산 면에서 유리한 새로운 제조방법 개발이 요구되어 왔다.Accordingly, it has been desired to produce a high purity gadobutrol in a high yield without a complicated purification process, and to develop a new production method advantageous from the viewpoint of mass production.
본 발명의 목적은 간단하고 온화한 공정만으로 고 순도의 가도부트롤을 고수율로 제조하는 방법을 제공하는 것이다. It is an object of the present invention to provide a method for producing a high purity gadobutrol in high yield only by a simple and mild process.
본 발명의 목적을 달성하기 위하여, 본 발명은 가도부트롤의 새로운 제조방법을 제공한다.In order to accomplish the object of the present invention, the present invention provides a new method for preparing goad boutrol.
본 발명의 제조방법은 (S1) 하기 화학식 2로 표시되는 화합물 또는 그의 염으로부터 하기 화학식 3으로 표시되는 화합물을 제조하는 단계, (S2) 상기 화학식 3으로 표시되는 화합물로부터 하기 화학식 4로 표시되는 화합물을 제조하는 단계 및 (S3) 상기 화학식 4로 표시되는 화합물로부터 하기 화학식 1로 표시되는 화합물을 제조하는 단계를 포함한다.(S1) preparing a compound represented by the following formula (3) from a compound represented by the following formula (2) or a salt thereof, (S2) preparing a compound represented by the formula And (S3) preparing a compound represented by the formula (1) from the compound represented by the formula (4).
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
{단, R은 C1-C4의 직쇄 또는 분지형 알킬이다}(Wherein R is C1-C4 linear or branched alkyl)
이하에서는 각 단계에 대하여 상세히 설명한다.
Each step will be described in detail below.
(( S1S1 ) 단계 : ) step : 카르복시메틸화Carboxymethylation 반응 reaction
본 발명의 제조방법에 있어서, 상기 (S1) 단계는 상기 화학식 2의 화합물 또는 그의 염과 하기 화학식 5의 화합물을 반응(카르복시메틸화)시켜 상기 화학식 3의 화합물을 제조하는 단계이다.In step (S1), the compound of formula (2) or salt thereof is reacted with a compound of formula (5) to produce a compound of formula (3).
[화학식 5][Chemical Formula 5]
{단, R은 C1-C4의 직쇄 또는 분지형 알킬이고, X는 할로겐, TsO- 또는 MsO-이다}{Where, R is a straight or branched alkyl of C1-C4, X is halogen, TsO - or MsO - a}
본 발명의 바람직한 구체예에 따르면, 상기 (S1) 단계의 상기 화학식 2의 화합물 또는 그의 염은 하기 화학식 2-1의 4 염산염일 수 있다.According to a preferred embodiment of the present invention, the compound of formula (2) or its salt in step (S1) may be a dihydrochloride of formula (2-1).
[화학식 2-1][Formula 2-1]
또한, 본 발명의 바람직한 구체예에 따르면, 상기 (S1) 단계의 상기 화학식 3의 화합물은 R이 t-부틸인 하기 화학식 3-1의 화합물일 수 있다. According to a preferred embodiment of the present invention, the compound of Formula 3 in Step (S1) may be a compound of Formula 3-1 wherein R is t-butyl.
[화학식 3-1][Formula 3-1]
또한, 본 발명의 바람직한 구체예에 따르면, 상기 화학식 5의 화합물은 X가 Br이고 R이 t-부틸인 하기 화학식 5-1의 화합물일 수 있다. According to a preferred embodiment of the present invention, the compound of Formula 5 may be a compound of Formula 5-1, wherein X is Br and R is t-butyl.
[화학식 5-1][Formula 5-1]
상기 (S1) 단계는 알킬화(카르복실메틸화) 반응에서 통상적으로 사용되는 유기용매 존재 하에 반응을 수행할 수 있다. 바람직하게는 물 및 C4-C11의 에테르의 혼합용매를 사용할 수 있으며, 보다 바람직하게는 물 및 테트라하이드로퓨란(THF)의 혼합용매를 사용할 수 있다. 다만, 이에 한정되지 않는다. The step (S1) may be carried out in the presence of an organic solvent ordinarily used in an alkylation (carboxylmethylation) reaction. Preferably, a mixed solvent of water and an ether of C4-C11 can be used, and more preferably, a mixed solvent of water and tetrahydrofuran (THF) can be used. However, the present invention is not limited thereto.
또한, 상기 (S1) 단계는 염기, 특히 무기염기 존재 하에 반응을 수행할 수 있다. 바람직하게는 탄산칼륨(K2CO3), 탄산수소나트륨(NaHCO3), 탄산수소칼륨(KHCO3) 또는 이들의 혼합물의 약염기를 사용할 수 있으며, 보다 바람직하게는 탄산칼륨을 사용할 수 있다. 다만, 이에 한정되지 않는다.In addition, the step (S1) may be carried out in the presence of a base, particularly an inorganic base. Preferably, a weak base of potassium carbonate (K 2 CO 3 ), sodium hydrogen carbonate (NaHCO 3 ), potassium hydrogen carbonate (KHCO 3 ), or a mixture thereof may be used, and more preferably potassium carbonate may be used. However, the present invention is not limited thereto.
상기 (S1) 단계의 반응은 50 내지 80 ℃에서 수행될 수 있으며, 바람직하게는 65 내지 70 ℃에서 수행될 수 있으며, 보다 바람직하게는 63 내지 68 ℃에서 수행될 수 있다. 다만, 이에 한정되지 않는다.The reaction of step (S1) may be carried out at 50 to 80 ° C, preferably at 65 to 70 ° C, and more preferably at 63 to 68 ° C. However, the present invention is not limited thereto.
본 발명의 바람직한 구체 예에 따르면, 상기 (S1) 단계는 상기 화학식 3의 화합물의 결정화 단계를 더 포함할 수 있다. According to a preferred embodiment of the present invention, the step (S1) may further comprise the step of crystallizing the compound of the formula (3).
상기 결정화 단계에서 사용되는 결정화 용매는 메틸렌클로라이드, C4-C11 에테르, C4-C8 알케인 또는 이들의 혼합물을 사용할 수 있으며, 메틸렌클로라이드 및 n-헥산의 혼합물을 사용하는 것이 바람직하다. The crystallization solvent used in the crystallization step may be methylene chloride, C4-C11 ether, C4-C8 alkane, or a mixture thereof, and it is preferable to use a mixture of methylene chloride and n-hexane.
상기 (S1) 단계로부터 상기 화학식 3의 화합물을 99% 이상, 바람직하게는 99.5% 이상, 보다 바람직하게는 99.7% 이상의 고순도로 수득할 수 있다.From step (S1), the compound of formula (3) can be obtained at a purity of 99% or more, preferably 99.5% or more, and more preferably 99.7% or more.
(( S2S2 ) 단계 : 산성 가수분해 반응) Step: Acid hydrolysis reaction
본 발명의 제조방법에 있어서, 상기 (S2) 단계는 (S1) 단계에서 고 순도로 수득된 화학식 3의 화합물을 산성 가수분해 반응시켜 화학식 4의 화합물(부트롤)을 고 순도로 제조하는 단계이다.In the production process of the present invention, the step (S2) is a step of acid-hydrolyzing the compound of formula (3) obtained in high purity in step (S1) to prepare a compound of formula (4) .
상기 산성 가수분해 반응은 에스테르의 통상적인 산성 가수분해 반응조건을 이용하여 수행할 수 있다. 바람직하게는 상기 화학식 3의 화합물에 묽은 염산 수용액 또는 묽은 황산 수용액을 가하여 수행할 수 있다.The acidic hydrolysis reaction can be carried out using conventional acidic hydrolysis conditions of the ester. Preferably, the compound of formula (3) may be added by adding dilute hydrochloric acid aqueous solution or dilute sulfuric acid aqueous solution.
또한, 상기 가수분해 반응은 50 내지 70 ℃에서 수행할 수 있으며, 바람직하게는 55 내지 65 ℃에서 수행할 수 있으며, 보다 바람직하게는 57 내지 63 ℃에서 수행될 수 있다. 다만, 이에 한정되지 않는다.In addition, the hydrolysis reaction can be carried out at 50 to 70 ° C, preferably 55 to 65 ° C, more preferably 57 to 63 ° C. However, the present invention is not limited thereto.
본 발명의 바람직한 구체예에 따르면, 상기 (S2) 단계는 레진을 사용하여 상기 화학식 4의 화합물을 정제하는 단계를 포함할 수 있다. 본 발명에 있어서, 상기 레진의 사용량은 약 4 내지 약 8 v/w이 바람직하며, 약 5 v/w이 가장 바람직하다. 따라서, 본 발명의 제조방법은 레진 사용량이 적으므로 추가 시설이 필요 없으며 생산단가가 높은 장점이 있다.According to a preferred embodiment of the present invention, the step (S2) may include the step of purifying the compound of Formula 4 using a resin. In the present invention, the amount of the resin to be used is preferably about 4 to about 8 v / w, and most preferably about 5 v / w. Therefore, the manufacturing method of the present invention is advantageous in that an additional facility is not required because the amount of resin used is small and the production cost is high.
또한, 본 발명의 바람직한 구체예에 따르면, 상기 (S2) 단계는 결정화 단계를 더 포함할 수 있다.Also, according to a preferred embodiment of the present invention, the step (S2) may further comprise a crystallization step.
상기 결정화 단계에서 사용되는 용매는 메탄올, 아세톤 또는 이들의 혼합물을 사용할 수 있으며, 메탄올 및 아세톤의 혼합용매를 사용하는 것이 바람직하다.The solvent used in the crystallization step may be methanol, acetone or a mixture thereof, and it is preferable to use a mixed solvent of methanol and acetone.
상기 (S2) 단계로부터 상기 화학식 4의 화합물(부트롤)을 90% 이상, 바람직하게는 95% 이상, 보다 바람직하게는 98% 이상의 고 순도로 수득할 수 있다.From step (S2), the compound of formula (4) (butrol) can be obtained at a high purity of 90% or more, preferably 95% or more, more preferably 98% or more.
(( S3S3 ) 단계 : 가돌리늄 ) Step: Gadolinium 착물Complex 형성 formation
본 발명의 제조방법에 있어서, 상기 (S3) 단계는 (S2) 단계에서 고순도로 수득된 화학식 4의 화합물(부트롤)에 가돌리늄 이온 공급원을 반응시켜 가돌리늄 착물인 가도부트롤을 제조하는 단계이다.In step (S3), the gadolinium ion source is reacted with the compound (4) of formula (4) obtained in high purity in step (S2) to prepare gadobutrol, which is a gadolinium complex.
상기 가돌리늄 이온 공급원은 가돌리늄 이온을 공급할 수 있는 모든 화합물을 사용할 수 있으며, 가돌리늄옥사이드, 가돌리늄아세테이트 또는 가돌리늄클로라이드를 사용할 수 있다. 바람직하게는 가돌리늄옥사이드를 사용할 수 있다. 다만, 이에 한정되지 않는다.The gadolinium ion source may be any compound capable of supplying gadolinium ion, and gadolinium oxide, gadolinium acetate or gadolinium chloride may be used. Preferably, gadolinium oxide can be used. However, the present invention is not limited thereto.
상기 (S3) 단계의 반응은 80 내지 100℃에서 수행될 수 있으며, 바람직하게는 85 내지 95 ℃에서 수행될 수 있으며, 보다 바람직하게는 87 내지 93 ℃에서 수행될 수 있다. 다만, 이에 한정되지 않는다.The reaction of step (S3) can be carried out at 80 to 100 ° C, preferably 85 to 95 ° C, more preferably 87 to 93 ° C. However, the present invention is not limited thereto.
상기 (S3) 단계에서 가도부트롤의 결정화 단계를 더 포함할 수 있다.The step (S3) may further include a crystallization step of the Gauged Burol.
상기 (S3) 단계로부터 상기 화학식 1의 화합물(가도부트롤)을 99% 이상, 바람직하게는 99.5% 이상, 보다 바람직하게는 99.9% 이상의 고 순도로 수득할 수 있다.From step (S3), the compound of formula 1 (Gardobutrol) can be obtained at a high purity of 99% or more, preferably 99.5% or more, more preferably 99.9% or more.
본 발명의 바람직한 구체 예에 따르면, 가도부트롤은 하기 반응식 1로 표시되는 방법에 의해 제조될 수 있다.According to a preferred embodiment of the present invention, the gadobutrol can be prepared by the method represented by the following Reaction Scheme 1.
[반응식 1][Reaction Scheme 1]
본 발명의 제조방법은 간단하고 온화한 공정만으로 고 순도의 가도부트롤을 고 수율로 제조할 수 있는 작용효과를 나타낸다.The production process of the present invention exhibits the action and effect that high purity gadobutrol can be produced at a high yield only by a simple and mild process.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시 예를 제시한다. 그러나 하기의 실시 예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다. Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.
또한, 이하에서 언급된 시약 및 용매는 특별한 언급이 없는 한 Sigma-Aldrich Korea로부터 구입한 것이며, IR은 Jasco 사의 FT-IR 4100 series를 사용하여 측정하였으며, HPLC는 Agilent Technoliges 사의 1200 Series를 사용하여 측정하였으며, 1H NMR은 Varian Mercury Instrument(배리안머큐리)사의 Oxford NMR 300MHz Spectrometer를 사용하여 측정하였다. 순도는 HPLC의 면적 %로 측정하였다.
The reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea unless otherwise noted. IR was measured using a FT-IR 4100 series from Jasco. HPLC was measured using an Agilent Technoliges 1200 series And 1 H NMR was measured using a Oxford NMR 300 MHz Spectrometer from Varian Mercury Instrument (Varian Mercury). Purity was determined by area% of HPLC.
실시예Example 1 One
단계 1 : Step 1: 터트Rat -부틸-2,2',2''-(10-(1,3,4--2,2 ', 2 "-( 10- (1,3,4- 트리히드록시부탄Trihydroxybutane -2-일)-1,4,7,10-테트라아자시클로도데칸-1,4,7-트리일)트리아세테이트의 제조-2-yl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate
3-(1,4,7,10-테트라아자시클로도데칸-1-일)부탄-1,2,4-트리올 4 염산염 (100 g, 0.2368 mol)을 정제수 500 ml와 테트라히드로퓨란 1500 ml에 용해 교반한 후 상온에서 탄산칼륨 (327 g, 2.3684 mol)을 첨가하고 터트-부틸브로모아세테이트 (143.2 g, 0.434 mmol)을 천천히 투입하였다. 투입이 완료되면 63 ~ 68 ℃에서 반응을 진행하고 반응이 완료되면 정제수 1000 ml를 투입하고 교반한 후 수층을 분리하였다. 분리한 유기층은 감압 하에 농축하여 제거한 다음 정제수 1500 ml와 톨루엔 1000 ml를 사용하여 유기층을 분리하고 분리한 유기층에 염산 550 ml를 투입하여 수층을 분리하였다. 분리한 수층에 메틸렌클로라이드 500 ml를 투입하고 탄산나트륨 (100 g)을 이용하여 pH를 9.3 ~ 9.8로 조절한 뒤 유기층을 분리하였다. 분리한 유기층은 10 % 소금물로 세척하여 유기층을 분리하고 탈수를 진행한 뒤 감압 하에 농축하였다. 농축 잔사에 메틸렌클로라이드 (400 ml)와 n-헥산 (1600 ml)을 사용하여 생성된 고체를 여과, 건조하여 터트-부틸-2,2',2''-(10-(1,3,4-트리히드록시부탄-2-일)-1,4,7,10-테트라아자시클로도데칸-1,4,7-트리일)트리아세테이트 117.3 g을 얻었다.1,2,3,4-triol dihydrochloride (100 g, 0.2368 mol) was dissolved in 500 ml of purified water and 1500 ml of tetrahydrofuran And potassium carbonate (327 g, 2.3684 mol) was added thereto at room temperature. Then, tert-butyl bromoacetate (143.2 g, 0.434 mmol) was slowly added thereto. When the reaction was completed, 1000 ml of purified water was added, stirred, and the aqueous layer was separated. The separated organic layer was concentrated under reduced pressure and then removed. The organic layer was separated using 1500 ml of purified water and 1000 ml of toluene, and 550 ml of hydrochloric acid was added to the separated organic layer to separate the aqueous layer. 500 ml of methylene chloride was added to the separated aqueous layer, the pH was adjusted to 9.3 to 9.8 using sodium carbonate (100 g), and the organic layer was separated. The separated organic layer was washed with 10% brine, the organic layer was separated, dehydrated, and concentrated under reduced pressure. The resulting residue was filtered and dried using methylene chloride (400 ml) and n-hexane (1600 ml) to obtain tert-butyl-2,2 ', 2 "- (10- -Trihydroxybutan-2-yl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate was obtained.
수율 80%, 순도 99.7%Yield 80%, purity 99.7%
1H-NMR(CDCl3, 300MHz): δ (ppm) 1.46(s, 9H), 1.90~3.10(m, 11H), 3.20~3.80(m, 17H) 1 H-NMR (CDCl 3 , 300 MHz):? (Ppm) 1.46 (s, 9H), 1.90-3.10 (m, 11H), 3.20-3.80
Infrared spectrum(KBr, cm-1): 3350, 2980, 2960, 2860, 2820, 1730, 1455
Infrared spectrum (KBr, cm -1 ): 3350, 2980, 2960, 2860, 2820, 1730, 1455
단계 2 : 2,2',2''-(10-(1,3,4-Step 2: 2,2 ', 2 "- (10- (1,3,4- 트리히드록시부탄Trihydroxybutane -2-일)-1,4,7,10-Yl) -1,4,7,10- 테트라아자Tetraaza 시클로도데칸-1,4,7-트리일)Cyclododecane-1,4,7-triyl) 트리아세트산Triacetic acid ( ( 부트롤Butrol )의 제조)
단계 1에서 제조된 터트-부틸-2,2',2''-(10-(1,3,4-트리히드록시부탄-2-일)-1,4,7,10-테트라아자시클로도데칸-1,4,7-트리일)트리아세테이트 (30 g, 0.048 mol)을 정제수 60 ml에 용해 교반하면서 내부 온도를 57 ~ 63 ℃로 승온하고, 승온이 완료되면 미리 제조해 둔 정제수 60 ml와 황산 6 ml의 혼합액을 적가하고 동일 온도에서 4 시간 반응을 진행하고 반응 종결을 확인하고 실온 (20 ~ 25 ℃)으로 냉각하였다. 냉각완료 후 레진 (5 v/w) 처리 후 농축을 진행하였다. 농축 잔사에 메탄올 (90 ml)과 아세톤 (300 ml)을 사용하여 생성된 결정을 여과하고 아세톤으로 세척하였다. 여과한 결정을 내부 온도 50 ℃에서 진공건조하여 2,2',2''-(10-(1,3,4-트리히드록시부탄-2-일)-1,4,7,10-테트라아자시클로도데칸-1,4,7-트리일)트리아세트산 20.1 g을 얻었다.Butyl-2,2 ', 2 "- (10- (1,3,4-trihydroxybutan-2-yl) -1,4,7,10-tetraazacyclodio Decane-1,4,7-triyl) triacetate (30 g, 0.048 mol) was dissolved in 60 ml of purified water and the internal temperature was raised to 57 to 63 ° C while stirring. When the temperature was elevated, purified water And sulfuric acid (6 ml) was added dropwise, and the reaction was continued at the same temperature for 4 hours. The reaction was terminated and cooled to room temperature (20 to 25 ° C). After cooling, resin (5 v / w) was treated and concentrated. The resulting crystals were filtered using methanol (90 ml) and acetone (300 ml), and washed with acetone. The filtered crystals were dried in vacuo at an internal temperature of 50 ° C to give 2,2 ', 2 "- (10- (1,3,4-trihydroxybutan-2-yl) -1,4,7,10- Azacyclododecane-1,4,7-triyl) triacetic acid (20.1 g).
수율 92%, 순도 98%Yield 92%, purity 98%
1H-NMR(CDCl3,300MHz): δ (ppm) 1.92~3.15(m, 11H), 3.23~3.88(m, 17H) 1 H-NMR (CDCl 3 , 300 MHz):? (Ppm) 1.92-3.15 (m, 11H), 3.23-3.88 (m,
Infrared spectrum(KBr, cm-1): 3350, 2980, 2960, 2860, 2820, 1730, 1455
Infrared spectrum (KBr, cm -1 ): 3350, 2980, 2960, 2860, 2820, 1730, 1455
단계 3 : 10-(2,3-디히드록시-Step 3: Preparation of 10- (2,3-dihydroxy- 1(히드록시메틸)프로필1 (hydroxymethyl) propyl )-1,4,7,10-) -1,4,7,10- 테트라아자Tetraaza 시클로도데칸-1,4,7-Cyclododecane-1,4,7- 트리아세트산의Triacetic 가돌리늄 gadolinium 착물(가도부트롤)의Complex (of the goat troll) 제조 Produce
단계 2에서 제조된 2,2',2''-(10-(1,3,4-트리히드록시부탄-2-일)-1,4,7,10-테트라아자시클로도데칸-1,4,7-트리일)트리아세트산 (15.4 g, 0.0342 mol)을 정제수 77 ml에 용해 교반하고, 가돌리늄옥사이드(8.67 g, 0.0240 mol)을 투입하였다. 내부온도를 87 ~ 93 ℃로 승온하고 동일 온도에서 1 시간을 교반하였다. 반응 종결을 확인한 후 반응 액을 규조토를 이용하여 여과를 진행하였다. 여과액에 레진을 넣고 교반 후 여과를 진행하고 탈색처리 후 감압 하에 농축하였다. 농축 잔사에 정제수 7.7 ml를 투입하고 내부온도 70 ~ 75 ℃에서 2 시간 교반하였다. 용해 완료 후 에탄올 121.5 ml를 넣고 3 시간 동안 환류 교반하였다. 실온 (20 ~ 25 ℃)으로 냉각하고 동일 온도에서 1 시간 동안 교반한 후 질소 대기 하에서 여과하였다. 여과한 결정을 내부 온도 50 ℃ 이하에서 진공건조하여 10-(2,3-디히드록시-1(히드록시메틸)프로필)-1,4,7,10-테트라아자시클로도데칸-1,4,7-트리아세트산의 가돌리늄 16.2 g을 얻었다.2, 2 "-( 10- (1,3,4-trihydroxybutan-2-yl) -1,4,7,10-tetraazacyclododecane- 4,7-triyl) triacetic acid (15.4 g, 0.0342 mol) was dissolved in 77 ml of purified water and stirred, and gadolinium oxide (8.67 g, 0.0240 mol) was added thereto. The internal temperature was raised to 87 ~ 93 < 0 > C and stirred at the same temperature for 1 hour. After confirming the termination of the reaction, the reaction solution was filtered using diatomaceous earth. The resin was added to the filtrate, stirred, filtered, decolorized, and concentrated under reduced pressure. 7.7 ml of purified water was added to the concentrated residue and stirred at an internal temperature of 70 to 75 ° C for 2 hours. After completion of the dissolution, 121.5 ml of ethanol was added and the mixture was refluxed and stirred for 3 hours. The mixture was cooled to room temperature (20 to 25 ° C), stirred at the same temperature for 1 hour, and then filtered under a nitrogen atmosphere. The filtered crystals were dried under vacuum at an internal temperature of 50 DEG C or lower to obtain 10- (2,3-dihydroxy-1 (hydroxymethyl) propyl) -1,4,7,10-tetraazacyclododecane-1,4 , 16.2 g of gadolinium of 7-triacetic acid was obtained.
수율 78.3%, 순도 99.99% Yield 78.3%, purity 99.99%
Infrared spectrum(KBr, cm-1): 3560, 3280, 2980, 2975, 2940, 2920, 2880, 2870, 1650, 1600, 1380
Infrared spectrum (KBr, cm -1 ): 3560, 3280, 2980, 2975, 2940, 2920, 2880, 2870, 1650, 1600, 1380
비교예Comparative Example 1 One
종래기술 (Inorg. Chem. 1997, 36, 6086-6093)에 개시된 스킴 1에 따라 가도부트롤을 제조하였다.Gadobutrol was prepared according to Scheme 1 disclosed in the prior art (Inorg. Chem. 1997, 36, 6086-6093).
수율 65%, 순도 95.98%Yield 65%, purity 95.98%
Infrared spectrum(KBr, cm-1): 실시예 1과 동일함.
Infrared spectrum (KBr, cm -1 ): Same as Example 1.
비교예Comparative Example 2 2
종래기술 (Inorg. Chem. 1997, 36, 6086-6093)에 개시된 스킴 2에 따라 가도부트롤을 제조하였다.Gadobutrol was prepared according to Scheme 2 disclosed in the prior art (Inorg. Chem. 1997, 36, 6086-6093).
수율 63%, 순도 93.57%Yield 63%, purity 93.57%
Infrared spectrum(KBr, cm-1): 실시예 1과 동일함.Infrared spectrum (KBr, cm -1 ): Same as Example 1.
Claims (14)
(S2) 상기 화학식 3으로 표시되는 화합물로부터 하기 화학식 4로 표시되는 화합물을 제조하는 단계; 및
(S3) 상기 화학식 4로 표시되는 화합물로부터 하기 화학식 1로 표시되는 화합물을 제조하는 단계;
를 포함하고,
상기 (S1) 단계는 상기 화학식 2의 화합물과 하기 화학식 5의 화합물을 반응시키는 단계를 포함하며,
상기 (S2) 단계는 산성 가수분해 반응으로 수행되고,
상기 (S3) 단계는 상기 화학식 4의 화합물과 가돌리늄옥사이드, 가돌리늄아세테이트 또는 가돌리늄클로라이드를 반응시키는 것인 가도부트롤의 제조방법:
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
{단, R은 C1-C4의 직쇄 또는 분지형 알킬이고, X는 할로겐, TsO- 또는 MsO-이다}(S1) preparing a compound represented by the following formula (3) from a compound represented by the following formula (2) or a salt thereof;
(S2) preparing a compound represented by the formula (4) from the compound represented by the formula (3); And
(S3) preparing a compound represented by the formula (1) from the compound represented by the formula (4);
Lt; / RTI >
The step (S1) comprises reacting the compound of Formula 2 with a compound of Formula 5,
The step (S2) is performed in an acidic hydrolysis reaction,
Wherein the step (S3) is a step of reacting the compound of Formula 4 with gadolinium oxide, gadolinium acetate or gadolinium chloride,
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
{Where, R is a straight or branched alkyl of C1-C4, X is halogen, TsO - or MsO - a}
[화학식 2-1]
[Formula 2-1]
[화학식 3-1]
[Formula 3-1]
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| KR1020140190833A KR101653064B1 (en) | 2014-12-26 | 2014-12-26 | A Method for Gadobutrol |
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| PCT/KR2015/014301 WO2016105172A2 (en) | 2014-12-26 | 2015-12-28 | A method for preparing gadobutrol |
| CN201580058685.8A CN107001294B (en) | 2014-12-26 | 2015-12-28 | Method for preparing gadobutrol |
| ES15873699T ES2706319T3 (en) | 2014-12-26 | 2015-12-28 | A method of preparing gadobutrol |
| EP15873699.1A EP3204364B1 (en) | 2014-12-26 | 2015-12-28 | A method for preparing gadobutrol |
| JP2017533472A JP6419341B2 (en) | 2014-12-26 | 2015-12-28 | Method for producing gadobutrol |
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| KR20190079682A (en) | 2011-04-21 | 2019-07-05 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | Preparation of high-purity gadobutrol |
| KR101971435B1 (en) * | 2017-08-29 | 2019-04-24 | 주식회사 엔지켐생명과학 | Gadobutrol intermediate and method for preparing gadobutrol using the same |
| KR20190088793A (en) * | 2018-01-19 | 2019-07-29 | 주식회사 엔지켐생명과학 | Manufacturing method of calcobutrol |
| CN108299322B (en) * | 2018-02-07 | 2020-03-27 | 广州康瑞泰药业有限公司 | Method for preparing gadobutrol |
| KR101979836B1 (en) * | 2019-01-02 | 2019-05-21 | 동국생명과학 주식회사 | Process for the preparation of calcobutrol |
| CN113880850B (en) * | 2021-10-18 | 2022-10-04 | 苏州百灵威超精细材料有限公司 | Gadobutrol intermediate, preparation method and application in gadobutrol preparation |
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| KR100269081B1 (en) | 1992-06-04 | 2000-10-16 | 에바-마리아 시마-메이어, 얼설라 멜져, 마거, 하르트만 | Process for producing n-beta-hydroxy alkyl-tri-n-carboxyalkyl-1,4,7,10-tetraazacyclododecane and n-beta-hydroxyalkyl-tri-n-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives and their metal complexes |
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| DE4140779A1 (en) * | 1991-12-06 | 1993-06-09 | Schering Ag Berlin Und Bergkamen, 1000 Berlin, De | METHOD FOR PRODUCING MONO-N SUBSTITUTED TETRAAZAMACROCYCLES |
| DE4237943C2 (en) * | 1992-11-06 | 1997-10-23 | Schering Ag | Process for the preparation of metal complexes of N-beta-hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and N-beta-hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane Derivatives |
| DE102010023105A1 (en) * | 2010-06-04 | 2011-12-08 | Bayer Schering Pharma Aktiengesellschaft | Gadobutrol preparation in a one-pot process using DMF-acetal and N-methylimidazole |
| EP2457594A1 (en) * | 2010-11-05 | 2012-05-30 | Bracco Imaging S.p.A | Cest systems exhibiting a concentration independent responsiveness |
| KR20190079682A (en) * | 2011-04-21 | 2019-07-05 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | Preparation of high-purity gadobutrol |
| CN103613557B (en) * | 2013-10-18 | 2015-07-29 | 武汉利宝瑞医药科技有限公司 | A kind of preparation method of magnetic resonance imaging contrast agent gadobutrol |
| KR101693400B1 (en) * | 2014-09-17 | 2017-01-05 | 에스티팜 주식회사 | A Method for Preparing Calcobutrol |
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| KR100269081B1 (en) | 1992-06-04 | 2000-10-16 | 에바-마리아 시마-메이어, 얼설라 멜져, 마거, 하르트만 | Process for producing n-beta-hydroxy alkyl-tri-n-carboxyalkyl-1,4,7,10-tetraazacyclododecane and n-beta-hydroxyalkyl-tri-n-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivatives and their metal complexes |
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| WO2020040617A1 (en) | 2018-08-23 | 2020-02-27 | 에스티팜 주식회사 | Method of manufacturing gadobutrol |
| KR20200022648A (en) | 2018-08-23 | 2020-03-04 | 에스티팜 주식회사 | A method for preparing gadobutrol |
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